Pyrethroids are synthetic analogues of naturally occurring pyrethrum from the flower extracts of Chrysanthemum and are best known for their insecticidal activity and low toxicity to mammals. As such, they are widely used in the control of numerous arthropod pests, including insect vectors that transmit human disease. Beside the direct insecticidal activity of pyrethroids which is based on their ability to bind and hyper- activate voltage-gated sodium channels in the insect nervous system, remarkably, natural-occurring pyrethrum and volatile pyrethroids exhibit clear spatial repellency. In fact, the spatial repellency of these compounds is now being evaluated for human disease vector control. However, the molecular basis of the spatial repellency of pyrethroid remains elusive. The central hypothesis of the proposed work is that pyrethrum and volatile pyrethroids exert their spatial repellency by interacting with specific olfactory receptors independent of their sodium channel-based insecticidal activity. The specific aims of this new proposal are: 1) Identification of pyrethroid-responsive sensilla and olfaction receptors (OR) in Drosophila melanogaster. 2) Identification of pyrethroid-responsive sensilla and ORs in mosquitoes. 3) Determination of the role of pyrethroid-responsive ORs in spatial repellency. A combination of electrophysiology and molecular genetic methods will be used to test the hypothesis, with the final goal of identificatio of olfactory receptors that are responsible for spatial repellency of pyrethroids. The proposed research is innovative and pioneering in beginning to elucidate the molecular basis of repellency of insect vectors to pyrethrum and pyrethroids. The knowledge gained will form the foundation on which to build alternative insect vector control strategies based on spatial repellency, with th ultimate goal of enhancing the utility of pyrethroids and reducing disease transmission by insect vectors.